22-40411452-G-C

Variant names:

• chr22-40411452-G-C
• rs781098796
• NM_020831.6:c.3034C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020831.6(MRTFA):​c.3034C>G​(p.Leu1012Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,445,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MRTFA NM_020831.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 1 publications found

Genes affected

MRTFA (HGNC:14334): (myocardin related transcription factor A) The protein encoded by this gene interacts with the transcription factor myocardin, a key regulator of smooth muscle cell differentiation. The encoded protein is predominantly nuclear and may help transduce signals from the cytoskeleton to the nucleus. This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MRTFA Gene-Disease associations (from GenCC):

• immunodeficiency 66

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06723586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRTFA	NM_020831.6	c.3034C>G	p.Leu1012Val	missense_variant	Exon 15 of 15	ENST00000355630.10	NP_065882.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRTFA	ENST00000355630.10	c.3034C>G	p.Leu1012Val	missense_variant	Exon 15 of 15	1	NM_020831.6	ENSP00000347847.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247894 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000692 AC: 10 AN: 1445538 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 715630

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.000181 AC: 8 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.00 AC: 0 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099314

Other (OTH) AF: 0.0000168 AC: 1 AN: 59534

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 912 of the MKL1 protein (p.Leu912Val). This variant is present in population databases (rs781098796, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MKL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1682912). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T;T;T;T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.91	.;D;D;D;T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.067	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.35	N;.;N;N;.;.
REVEL	Benign	0.073
Sift	Benign	0.73	T;.;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.27	B;.;B;B;.;.
Vest4		0.34
MutPred		0.19		Loss of disorder (P = 0.1141);.;.;Loss of disorder (P = 0.1141);.;.;
MVP		0.19
MPC		0.31
ClinPred		0.31	T
GERP RS		4.8
Varity_R		0.075
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781098796; hg19: chr22-40807456;